ASCL1 regulates and cooperates with FOXA2 to drive terminal neuroendocrine phenotype in prostate cancer.

IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Shaghayegh Nouruzi, Takeshi Namekawa, Nakisa Tabrizian, Maxim Kobelev, Olena Sivak, Joshua M Scurll, Cassandra Jingjing Cui, Dwaipayan Ganguli, Amina Zoubeidi
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引用次数: 0

Abstract

Lineage plasticity mediates resistance to androgen receptor pathway inhibitors (ARPIs) and progression from adenocarcinoma to neuroendocrine prostate cancer (NEPC), a highly aggressive and poorly understood subtype. ASCL1 has emerged as a central regulator of the lineage plasticity driving neuroendocrine differentiation. Here, we showed that ASCL1 was reprogrammed in ARPI-induced transition to the terminal NEPC and identified that the ASCL1 binding pattern tailored the expression of lineage-determinant transcription factor combinations that underlying discrete terminal NEPC identity. Notably, we identified FOXA2 as a major co-factor of ASCL1 in terminal NEPC, which is highly expressed in ASCL1-driven NEPC. Mechanistically, FOXA2 and ASCL1 interacted and worked in concert to orchestrate terminal neuronal differentiation. We identified that Prospero-Related Homeobox 1 was a target of ASCL1 and FOXA2. Targeting prospero-related homeobox 1 abrogated neuroendocrine characteristics and led to a decrease in cell proliferation in vitro and tumor growth in vivo. Our findings provide insights into the molecular conduit underlying the interplay between different lineage-determinant transcription factors to support the neuroendocrine identity and nominate prospero-related homeobox 1 as a potential target in ASCL1 high NEPC.

ASCL1 调节并与 FOXA2 合作驱动前列腺癌的终末神经内分泌表型。
系谱可塑性介导了对雄激素受体通路抑制剂(ARPIs)的耐受性以及腺癌向神经内分泌性前列腺癌(NEPC)的进展,NEPC是一种侵袭性很强的亚型,但人们对其了解甚少。ASCL1 已成为驱动神经内分泌分化的系可塑性的核心调节因子。在这里,我们发现 ASCL1 在 ARPI 诱导的向终末 NEPC 过渡的过程中被重新编程,并确定 ASCL1 的结合模式调整了决定系谱的转录因子组合的表达,这些转录因子组合是离散终末 NEPC 特性的基础。值得注意的是,我们发现 FOXA2 是 ASCL1 在末端 NEPC 中的主要辅助因子,它在 ASCL1 驱动的 NEPC 中高度表达。从机制上讲,FOXA2 和 ASCL1 相互作用,共同协调末端神经元的分化。我们发现繁荣相关同源框 1 是 ASCL1 和 FOXA2 的靶标。靶向 prospero-related homeobox 1 可抑制神经内分泌特征,减少体外细胞增殖和体内肿瘤生长。我们的研究结果让人们深入了解了支持神经内分泌特性的不同系决定性转录因子之间相互作用的分子渠道,并将繁荣相关同工酶1提名为ASCL1高NEPC的潜在靶点。
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来源期刊
JCI insight
JCI insight Medicine-General Medicine
CiteScore
13.70
自引率
1.20%
发文量
543
审稿时长
6 weeks
期刊介绍: JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.
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